They are locked by either a standard lock or a lock controlled by a nearby terminal, and require either lockpicking or hacking to unlock it. Inside may be a variety of items, including but not limited to caps, ammo, junk and weapons.

Safes in Fallout 3 and New Vegas are large black reinforced metal boxes, found either freestanding or installed into walls or floors. They are commonly somewhat concealed behind counters or desks, or covered up by since-ruined picture frames. Most safes will be found locked, but some can be found with open doors. However, opening a safe only brings up an inventory dialogue, and does not physically open the safe. Safe locks can range from Very Easy to Very Hard, though they tend towards the latter. The difficulty of the lock usually scales with the value of the loot contained inside; some safe loot is randomly generated, whereas other loot will be set, such as loot from quest rewards.

Safes permanently remain empty after being looted, giving the (usually false) appearance that they are safe storage containers for personal loot. In order to reset empty safes, you need to disable and then enable them with console commands. Finally, leave the current cell, save and then quit. After three days in game, the next time you return to the designated safe, it should be reloaded.

Safes owned by non-player characters will usually have a corresponding key that can either be pickpocketed, removed from their corpse, or occasionally given to you during a quest, such as A Manhandled Manservant.

Some safes also have a connected computer terminal. Usually, the player will need a lower Science skill to hack the terminal than Lockpick skill to open a given safe. When you have accessed the terminal, the command to unlock will be listed, and the lock will open.

Not every nearby terminal unlocks a safe; additionally, some safes may only be opened by terminals, such as the safe in Jiggs' Loot.